The Plasmodium species that cause malaria are obligate intracellular parasites, and disease symptoms occur when these parasites replicate in human blood. Despite the risk of immune detection, the parasite delivers proteins that bind to host receptors on the cell surfaces of infected erythrocytes. In the causative parasite of the most deadly form of malaria in humans, Plasmodium falciparum , RIFINs form the largest family of surface proteins displayed by erythrocytes 1 . Some RIFINs can bind to inhibitory immune receptors, and these RIFINs act as targets for unusual antibodies that contain a LAIR1 ectodomain 2 – 4 or as ligands for LILRB1 5 . RIFINs stimulate the activation of and signalling by LILRB1 5 , which could potentially lead to the dampening of human immune responses. Here, to understand how RIFINs activate LILRB1-mediated signalling, we determine the structure of a RIFIN bound to LILRB1. We show that this RIFIN mimics the natural activating ligand of LILRB1, MHC class I, in its LILRB1-binding mode. A single mutation in the RIFIN disrupts the complex, blocks LILRB1 binding of all tested RIFINs and abolishes signalling in a reporter assay. In a supported lipid bilayer system, which mimics the activation of natural killer (NK) cells by antibody-dependent cell-mediated cytotoxicity, both RIFIN and MHC are recruited to the immunological synapse of NK cells and reduce the activation of NK cells, as measured by the mobilization of perforin. Therefore, LILRB1-binding RIFINs mimic the binding mode of the natural ligand of LILRB1 and suppress the function of NK cells. The structure of a RIFIN–LILRB1 complex reveals that a subset of RIFINs of Plasmodium falciparum mimics the binding mode of the natural ligand of human LILRB1 and suppress the function of natural killer cells in humans.

中文翻译：

---

RIFIN介导的疟疾中LILRB1激活的结构基础

引起疟疾的疟原虫属专性细胞内寄生虫，当这些寄生虫在人类血液中复制时就会出现疾病症状。尽管存在免疫检测的风险，但寄生虫会传递与受感染红细胞细胞表面宿主受体结合的蛋白质。在人类最致命的疟疾形式恶性疟原虫的致病寄生虫中，RIFIN 形成了红细胞显示的最大的表面蛋白家族 1 。一些 RIFINs 可以与抑制性免疫受体结合，这些 RIFINs 作为含有 LAIR1 胞外域 2 – 4 的不寻常抗体的靶标或作为 LILRB1 5 的配体。RIFINs 刺激 LILRB1 5 的激活和信号传导，这可能会导致人类免疫反应的抑制。在这里，为了了解 RIFINs 如何激活 LILRB1 介导的信号传导，我们确定了绑定到 LILRB1 的 RIFIN 的结构。我们表明，这种 RIFIN 在其 LILRB1 结合模式下模拟了 LILRB1、MHC I 类的天然激活配体。RIFIN 中的单个突变会破坏复合物，阻止所有测试的 RIFIN 与 LILRB1 结合，并消除报告基因检测中的信号传导。在支持的脂质双层系统中，通过抗体依赖性细胞介导的细胞毒性模拟自然杀伤 (NK) 细胞的激活，RIFIN 和 MHC 都被募集到 NK 细胞的免疫突触并减少 NK 细胞的激活，如测量通过调动穿孔素。因此，结合 LILRB1 的 RIFIN 模拟了 LILRB1 天然配体的结合模式，抑制了 NK 细胞的功能。